Transcript Fundamentals of Cell Biology

Fundamentals of Cell Biology
Chapter 13: The Birth and Death of Cells
Chapter Summary: The Big Picture (1)
• Chapter foci:
– How cells make the decision to begin moving
through the stages of replication, and why some
cells never make this journey
– How cells decide to die
Chapter Summary: The Big Picture (2)
• Section topics:
– New cells arise from parental cells that
complete the cell cycle
– Multicellular organisms contain a cell selfdestruct program that keeps them healthy
New cells arise from parental cells that
complete the cell cycle
• Key Concepts (1):
– Cells divide by following carefully scripted program
of molecular events collectively called the cell cycle.
– The cell cycle is subdivided into five phases named
G1, S, G2, M, and G0. Cells not actively dividing
reside in G1 or G0 phase.
– Progression through the cell cycle is under the
control of proteins that form checkpoints to monitor
whether the proper sequence of events is taking
place. Cells halt at these checkpoints until they
complete the necessary steps to continue.
New cells arise from parental cells that
complete the cell cycle
• Key Concepts (2):
– The G1/S checkpoint, called the restriction point or
start point, is where cells commit to completing cell
division. Proteins called cyclins play an important
role in advancing cells through checkpoints.
– Cell division takes place in ten steps.
The cell cycle is divided into five
phases
• “Resting” cells reside
in G0 or G1 phase
• Several checkpoints
define critical
decision-making
events in the cell
cycle
Figure 13.01:
The cell
cycle.
Figure 13.02:
Checkpoints
control
progression
through the
cell cycle.
Some of the
major
checkpoints
are shown.
“Point of no return”
The G2/M checkpoint is the trigger for largescale rearrangement of cellular architecture
• MPF
Figure 13.03: Early experiments characterizing the activity of
Mitosis Promoting Factor.
Activation of cyclin-CDK complexes
begins in G1 phase
Figure 13.04: Scientists discovered the first cyclins when they noted that high cyclin levels
with the onset of mitosis in embryos. Cyclin levels drop sharply after this.
Control by cyclin/CDK complexes
Figure 13.05: Distinct cyclin-cdk complexes control progression through cell cycle
checkpoints.
Cell cycle step 1: Signal transduction
initiates cell cycle progression.
Figure 13.06: The family of mitogen
activated protein kinases (MAPKs) and
their upstream regulatory proteins.
Figure 13.07: A simplified MAP
kinase signaling pathway.
Cell cycle step 2: Changes in gene
expression are required for progression
through the restriction point
• progression through the restriction point in
mammalian cells requires activation of at least
two cyclin/CDK complexes: cyclin D1/CDK4 (or
CDK6) and cyclin E/CDK2
• expression of most CDKs does not vary much
throughout the cycle, but without their
corresponding cyclins, they are not functional
Cell cycle step 3: Pro- and anti-growth
signaling networks converge at the G1/S
cyclin-CDK complexes
• Phosphorylation
• Binding by inhibitory
kinases
• Subcellular location
• Protein degradation
Figure 13.08: Summary of the cyclin/cdk
activation-inactivation cycle.
Cell cycle step 4: Active cyclin/CDKs
phosphorylate pocket proteins, which
activate E2Fs
Figure 13.09: The transcription
factor E2F is inactivated by Rb
binding.
Figure 13.10: Examples of positive (green) and
negative (red) feedback loops controlling E2F
function.
How E2Fs enhance expression of
some genes while suppressing
expression of others remains unclear
Figure 13.11: A model of how E2F transcription factors can suppress or activate gene
transcription.
Cell cycle step 5: The DNA replication
machinery is activated by protein kinases
Figure 13.12: Assembly of the prereplication complex.
DNA replication occurs in S phase
• 3 key steps
Figure 13.13: Activation of
the replication complex.
Cell cycle step 6: DNA integrity is ensured
by the G1/S, S/G2, and G2/M checkpoints
Figure 13.15: Growth arrest induced
by Chk1 and Chk2.
Figure 13.14: A current model for DNA repair.
Cell cycle step 7: Cells increase in size
during G2 phase
Figure 13.17: Wee1 mutation affects cell size. Compared to normal ("wild-type," WT)
yeast, Wee1 mutants grow to half normal size before dividing.
Cell cycle step 8: Cyclin B/CDK1 activation
drives cells through the G2/M checkpoint
Figure 13.18: A model for cell size control of
cell growth in yeast in G2.
Figure 13.19: A model for how
adhesion to ECM promotes cell growth
in mammalian cells.
Figure 13.20: Phosphorylation of Cdk1 primes it for activation but also keeps it in an
inactive state.
Cell cycle step 9: Chromosome alignment is
ensured by the mitotic spindle assembly
checkpoint
Figure 13.21: A model for anaphase promotion by APC/C.
Cell cycle step 10: Onset of cytokinesis is
timed to begin only after mitosis is complete
• Cytokinesis requires the contraction of the
contractile ring that lies just beneath the plasma
membrane, perpendicular to the long axis of the
mitotic spindle.
• It is important that the myosin motors in the ring
not activate until mitosis, including reconstitution
of the nuclear membrane, is complete.
Multicellular organisms contain a cell selfdestruct program that keeps them healthy
• Key Concepts:
– Cells die either by traumatic injury (necrosis) or by a
self-destruct program called apoptosis.
– Apoptosis begins through at least two molecular
mechanisms, called intrinsic and extrinsic
pathways.
– The family of proteins called caspases includes
proteases that promote the degradation of
organelles and cytosolic proteins during apoptosis.
Cells die in 2 different ways:
necrosis and apoptosis
Figure 13.22: Cellular damage can result in necrosis, as organelles swell and the plasma
membrane ruptures.
Apoptosis is a property of all animal cells
and some plant cells
Apotosis is voluntary
Figure 13.23: Sections of the interdigital web show cell death (dark-staining nuclei). This
cell death has the characteristics of apoptosis.
Apoptosis is induced via at least
2 different pathways
Figure 13.24: Ligation of death receptors
causes the recruitment of the adaptor
protein FADD to the intracellular region of
the death receptor.
Figure 13.25: E2F1 lies at the heart of the
growth-versus-death decision making
system.
Targets of pro- and anti-apoptotic
transcription factors are members
of bcl-2 family
Figure 13.26: The Bcl-2 family proteins
share up to four Bcl-2 homology domains
(BH) and can be antiapoptotic or
proapoptotic.
Figure 13.27: The Bcl-2 family of proteins
compete with members of the
antiapoptotoic group to access the
apoptotic group in an elaborate hierarchy.
Mitochondrial Outer Membrane
Permeabilization (MOMP)
Figure 13.28: Signals for the induction of apoptosis trigger changes in the Bcl-2 family proteins, which function to
inhibit or promote apoptosis. Activation of caspase 9 by the apoptososme. Insert, three views of apoptosome
structure as determined by electron microscopy.
Apoptosis triggers the activation of
special proteases: the caspases
Figure 13.29: Different types of vertebrate caspases are shown schematically.
The final changes
• Stereotypical morphological changes take place
during apoptosis
– karyorrhexis
• Apoptotic cells are cleared by phagocytosis